WO2017075341A1 - Dérivés d'imidazole fusionnés utilisés comme inhibiteurs d'ido/tdo - Google Patents

Dérivés d'imidazole fusionnés utilisés comme inhibiteurs d'ido/tdo Download PDF

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Publication number
WO2017075341A1
WO2017075341A1 PCT/US2016/059307 US2016059307W WO2017075341A1 WO 2017075341 A1 WO2017075341 A1 WO 2017075341A1 US 2016059307 W US2016059307 W US 2016059307W WO 2017075341 A1 WO2017075341 A1 WO 2017075341A1
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Prior art keywords
compound
butyl
butoxy
further embodiment
present application
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PCT/US2016/059307
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English (en)
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Ben C. Askew
Takeru Furuya
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Scifluor Life Sciences, Inc.
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Publication of WO2017075341A1 publication Critical patent/WO2017075341A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • indoleamine 2,3-dioxygenase also known as HSfDO or IDO
  • IDO degrades the indole moiety of tryptophan, serotonin, and melatonin, and initiates the production of neuroactive and immunoregulatory metabolites, collectively known as kynurenines.
  • kynurenines neuroactive and immunoregulatory metabolites
  • IDO has been shown to play a role in immunosuppression, tumor resistance and/or rejection, chronic infections, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhea), autoimmune diseases or disorders (such as rheumatoid arthritis), and immunologic tolerance and prevention of fetal rejection in utero.
  • Inhibitors of IDO can be used to activate T cells and therefore enhance T cell activation when the T cells are suppressed by pregnancy, malignancy, or a virus such as HIV. Inhibition of IDO may also be an important treatment strateg for patients with neurological or neuropsychiatric diseases or disorders such as depression. Accordingly, therapeutic agents aimed at suppression of tryptophan degradation by inhibiting IDO activity are desirable.
  • the compounds, compositions, and methods described in the present application address the current need for IDO inhibitors.
  • the present application relates to compounds and methods for the modulation (e.g. , inhibition) of the enzyme indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase (IDO/TDO). Further, the present application relates to methods of treating diseases and disorders in which IDO/TDO plays a role.
  • Compounds of the present application which include compounds of any of Formulae (I), (la), (lb), (Ic), (Id), and (II), are capable of modulating (e.g., inhibiting) the activity of the IDO/TDO enzyme.
  • the present application provides methods of treating a disease or disorder in which modulating (e.g. , inhibiting) the IDO/TDO activity plays a role in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof.
  • the present application relates to a compound of Formula (I):
  • a compound of Formula (I) is a compound of any one of Formulae
  • the present application relates to a compound of Formula (II):
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present application relates to a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in modulating (e.g. , inhibiting) IDO/TDO.
  • the present application relates to a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in modulating (e.g. , inhibiting) the degradation of tryptophan and the production of N-formylkynurenine.
  • the present application relates to a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating immunosuppression mediated by IDO/TDO in a subject in need thereof.
  • the present application relates to a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating a disease or condition in which IDO/TDO plays a role in a subject in need thereof.
  • the present application relates to the use of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for modulating (e.g. , inhibiting)
  • the present application relates to the use of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for modulating (e.g. , inhibiting) the degradation of tryptophan and the production of N-formylkynurenine.
  • the present application relates to the use of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating immunosuppression mediated by IDO/TDO in a subject in need thereof.
  • the present application relates to the use of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a disease or condition in which IDO/TDO plays a role in a subject in need thereof .
  • the present application relates to a method for modulating (e.g. , inhibiting) IDO/TDO, comprising administering an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a
  • the present application relates to a method for modulating (e.g. , inhibiting) the degradation of tryptophan and the production of N-formylkynurenine, comprising administering an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • the present application relates to a method for treating
  • immunosuppression mediated by IDO/TDO in a subject in need thereof comprising administering to the subject an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • the present application relates to a method for treating a disease or condition in which IDO/TDO plays a role in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • the present application relates to a com ound of Formula (I)
  • W 1 is CR 1 or N
  • W 2 is CR 2 or N
  • W 3 is CR or N
  • W 4 is CR 4 or N
  • R 1 , R 2 , R 3 , and R 4 are each independently H, OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
  • Z 2 , and Z 3 are each independently a sihngle bond, CHR Z , or CH 2 CHR Z ; each R z is independently H, OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
  • Y is H, C1-C4 alkyl, or C1-C4 haloalkyl
  • n 0, 1, 2, or 3;
  • R 5 is OH, halogen, C1-C4 alkoxy, or C1-C4 haloalkoxy;
  • R 6 is H, OH, halogen, C1-C4 alkoxy, or C1-C4 haloalkoxy
  • R 7 and R 8 are each independently H, halogen, C1-C4 alkyl, or C1-C4 haloalkyl;
  • Y is C1-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) or C1-C4 haloalkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is substituted with one or more halogen (e.g.
  • Y is C 1 -C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). In another further embodiment, Y is methyl or ethyl. In a further embodiment, Y is methyl. In a further embodiment, Y is C 1 -C4 alkyl (e.g.
  • Y is CF 3 .
  • none of W 1 , W 2 , W 3 , and W 4 is N.
  • one of W 1 , W 2 , W 3 , and W 4 is N.
  • W 1 is N.
  • W 2 is N.
  • W 3 is N.
  • W 4 is N.
  • one of W 1 , W 2 , W 3 , and W 4 is N, and the remaining W 2 , W 3 , and W 4 are each CH.
  • one of W 1 , W 2 , W 3 , and W 4 is N, and at least one of the remaining of W 1 , W 2 , W 3 , and W 4 is not CH.
  • two of W 1 , W 2 , W 3 , and W 4 are N. In one embodiment, two of W 1 , W 2 , W 3 , and W 4 are N, and the remaining of W 1 , W 2 , W 3 , and W 4 are each CH. In one embodiment, two of W 1 , W 2 , W 3 , and W 4 are N, and at least one of the remaining of W 1 , W 2 , W 3 , and W 4 is not CH.
  • three of W 1 , W 2 , W 3 , and W 4 are N. In one embodiment, three of W 1 , W 2 , W 3 , and W 4 are N, and the remaining of W 1 , W 2 , W 3 , and W 4 is CH. In one embodiment, three of W 1 , W 2 , W 3 , and W 4 are N, and the remaining of W 1 , W 2 , W 3 , and W 4 is not CH.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • three of R 1 , R 2 , R 3 , and R 4 are H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • two of R 1 , R 2 , R 3 , and R 4 are H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • one of R 1 , R 2 , R 3 , and R 4 is H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • at least one of R 1 , R 2 , R 3 , and R 4 is OH, halogen, C 1 -C4 alkyl, C 1 -C4 alkoxy, C 1 -C4 haloalkyl, or C 1 -C4 haloalkoxy.
  • at least one of R 1 , R 2 , R 3 , and R 4 is OH.
  • at least one of R 1 , R 2 , R 3 , and R 4 is halogen.
  • At least one of R 1 , R 2 , R 3 , and R 4 is C 1 -C4 alkyl, C 1 -C4 alkoxy, C 1 -C4 haloalkyl, or C 1 -C4 haloalkoxy.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • at least one of R 1 , R 2 , R 3 , and R 4 is OH.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • at least one of R 1 , R 2 , R 3 , and R 4 is halogen (e.g., F, CI, Br, or I).
  • at least one of R 1 , R 2 , R 3 , and R 4 is F or CI.
  • at least one of R 1 , R 2 , R 3 , and R 4 is F.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • at least one of R 1 , R 2 , R 3 , and R 4 is C1-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, or t-butyl) or C1-C4 haloalkyl (e.g.
  • R 1 , R 2 , R 3 , and R 4 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F or CI.
  • At least one of R 1 , R 2 , R 3 , and R 4 is C1-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F.
  • C1-C4 alkyl e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • at least one of R 1 , R 2 , R 3 , and R 4 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i- butoxy, s-butoxy, or t-butoxy) or C1-C4 haloalkoxy (e.g.
  • R 1 , R 2 , R 3 , and R 4 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F or CI.
  • At least one of R 1 , R 2 , R 3 , and R 4 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i- butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • C1-C4 alkoxy e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i- butoxy, s-butoxy, or t-butoxy
  • Z 1 , Z 2 , and Z 3 are each a single bond.
  • one of Z 1 , Z 2 , and Z 3 is a single bond.
  • Z is a single bond.
  • Z 2 is a single bond.
  • Z 3 is a single bond.
  • one of Z 1 , Z 2 , and Z 3 is CHR Z .
  • Z 1 is CHR Z .
  • Z 2 is CHR Z .
  • Z 3 is CHR Z .
  • Z 2 , and Z 3 are each CHR Z .
  • one of Z 1 , Z 2 , and Z 3 is CF ⁇ CHR 2
  • Z 1 is CH 2 CHR Z .
  • Z 2 is CH 2 CHR Z .
  • Z 3 is CH 2 CHR Z .
  • each R z is H.
  • At least one R z is OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-
  • At least one R z is OH. [0044] In one embodiment, at least one R z is halogen (e.g. , F, CI, Br, or I). In a further embodiment, at least one R z is F or CI. In a further embodiment, at least one R z is F.
  • At least one R z is C 1 -C4 alkyl (e.g. , methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, or t-butyl) or C 1 -C4 haloalkyl (e.g., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • halogen e.g. , F, CI, Br, or I
  • At least one R z is C 1 -C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F or CI.
  • at least one R z is C 1 -C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F.
  • at least one R z is methyl.
  • At least one R z is C 1 -C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) or C1-C4 haloalkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • halogen e.g. , F, CI, Br, or I
  • At least one R z is C 1 -C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F or CI.
  • at least one R z is C 1 -C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • Y is H.
  • Y is C 1 -C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). In a further embodiment, Y is methyl.
  • Y is C 1 -C4 haloalkyl (e.g. , methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, or t-butyl, each of which is substituted with one or more halogen (e.g., F, CI, Br, or I)).
  • halogen e.g., F, CI, Br, or I
  • Y is C 1 -C4 alkyl (e.g., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F or CI.
  • Y is C 1 -C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F.
  • Y is CF 3 .
  • n 0.
  • n is 1, 2, or 3.
  • n is 0, 1, or 2. In a further embodiment, n is 1 or 2. In a further embodiment, n is i .
  • R 5 is OH
  • R 5 is halogen (e.g. , F, CI, Br, or I). In a further embodiment, R 5 is F or CI. In a further embodiment, R 5 is F. [0055] In one embodiment, R is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) or C1-C4 haloalkoxy (e.g.
  • R 5 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F or CI.
  • R 5 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F or CI.
  • R 5 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • R 6 is H.
  • R 6 is OH
  • R 6 is halogen (e.g. , F, CI, Br, or I). In a further embodiment, R 6 is F or CI. In a further embodiment, R 6 is F.
  • R 6 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) or C1-C4 haloalkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • R 6 is C1-C4 alkoxy (e.g.
  • R 6 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • R 7 and R 8 are each H.
  • R 7 is H and R 8 is halogen, C1-C4 alkyl, or C1-C4 haloalkyl.
  • R 8 is halogen (e.g., F, CI, Br, or I).
  • R 8 is F or CI.
  • R 8 is F.
  • R 8 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).
  • R 8 is C1-C4 haloalkyl (e.g.
  • R 8 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, or t-butyl) substituted with one or more F or CI.
  • R 8 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F or CI.
  • R 8 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F.
  • R 8 is H and R 7 is halogen, C1-C4 alkyl, or C1-C4 haloalkyl.
  • R 7 is halogen (e.g., F, CI, Br, or I).
  • R 7 is F or CI.
  • R 7 is F.
  • R 7 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).
  • R 7 is C1-C4 haloalkyl (e.g.
  • R 7 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, or t-butyl) substituted with one or more F or CI.
  • R 7 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F or CI.
  • R 7 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F.
  • R 7 and R 8 are independently halogen (e.g., F, CI, Br, or I), Ci- C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), or C1-C4 haloalkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • halogen e.g., F, CI, Br, or I
  • Ci- C4 alkyl e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-buty
  • the compound of Formula (I) comprises at least one fluorine atom. In a further embodiment, the compound of Formula (I) comprises at least two fluorine atoms. In a further embodiment, the compound of Formula (I) comprises at least three fluorine atoms.
  • At least one of Z Z , Z Y, R , R°, R , and R° is selected from a moiety comprising at least one fluorine atom.
  • at least one of Z 1 , Z 2 , Z 3 , Y, R 5 , R 7 , and R 8 is selected from a moiety comprising at least one fluorine atom.
  • at least one of Z 1 , Z 2 , Z 3 , Y, and R 5 is selected from a moiety comprising at least one fluorine atom.
  • At least two of R 1 , R 2 , R 3 , and R 4 are selected from a moiety comprising at least one fluorine atom.
  • any of the substituent groups described above for any of W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , Z 3 , R z , Y, n, R 5 , R 6 , R 7 , and R 8 can be combined with any of the substituent groups described above for the remainder of W 1 , W W W ⁇ R , R R R 4 , Z 1 , Z 2 , Z 3 , R z , Y, n, R 5 , R 6 , R 7 , and R 8 .
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • Z 1 , Z 2 , and Z 3 are each a single bond.
  • R 5 is OH.
  • R 5 is F. In a further embodiment, R 5 is OH and Y is C1-C4 alkyl or C1-C4 haloalkyl. In another further embodiment, R 5 is F and Y is C1-C4 alkyl or C1-C4 haloalkyl. In a further embodiment, Y is H and R 5 is CI, Br, I, C1-C4 alkoxy, or C1-C4 haloalkoxy. In a further embodiment, Y is H and R 5 is CI or Br. In a further embodiment, Y is H and R 5 is Ci- C4 alkoxy, or C1-C4 haloalkoxy.
  • W 1 , W 2 , W 3 , and W 4 is N, and Z 1 , Z 2 , and Z 3 are each a single bond.
  • R 5 is OH.
  • R 5 is F.
  • R 5 is OH and Y is C1-C4 alkyl or C1-C4 haloalkyl.
  • R 5 is F and Y is C1-C4 alkyl or C1-C4 haloalkyl.
  • Y is H and R 5 is CI, Br, I, C1-C4 alkoxy, or C1-C4 haloalkoxy. In a further embodiment, Y is H and R 5 is CI or Br. In a further embodiment, Y is H and R 5 is C1-C4 alkoxy, or C1-C4 haloalkoxy.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • Z 1 , Z 2 , and Z 3 are each a single bond.
  • R 5 is OH.
  • R 5 is F.
  • Y is C1-C4 alkyl or C1-C4 haloalkyl.
  • R 5 is OH and Y is C1-C4 alkyl or C1-C4 haloalkyl.
  • R 5 is OH and Y is C1-C4 haloalkyl.
  • R 5 is OH and Y is methyl or CF 3 .
  • R 5 is OH, Y is C1-C4 alkyl or C1-C4 haloalkyl, and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is OH, Y is C1-C4 haloalkyl, and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is OH, Y is methyl or CF 3 , and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F and Y is C1-C4 alkyl or C1-C4 haloalkyl.
  • R 5 is F and Y is C1-C4 haloalkyl.
  • R 5 is F and Y is methyl or CF 3 .
  • R 5 is F
  • Y is C1-C4 alkyl or C1-C4 haloalkyl
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • R is F
  • Y is C1-C4 haloalkyl
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F
  • Y is methyl or CF3, and R 1 , R 2 , R 3 , and R 4 are each H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • Z 1 is CHR Z
  • Z 2 and Z 3 are each a single bond.
  • R 5 is OH.
  • R 5 is OH
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F.
  • R 5 is F
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • Y is H.
  • R 5 is OH and Y is H.
  • R 5 is OH, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F and Y is H.
  • R 5 is F, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • Z 2 is CHR Z
  • Z 1 and Z 3 are each a single bond.
  • R 5 is OH.
  • R 5 is OH
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F.
  • R 5 is F
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • Y is H.
  • R 5 is OH and Y is H.
  • R 5 is OH, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F and Y is H.
  • R 5 is F, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • Z 3 is CHR Z
  • Z 1 and Z 2 are each a single bond.
  • R 5 is OH.
  • R 5 is OH
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • R is F.
  • R 5 is F
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • Y is H.
  • R 5 is OH and Y is H.
  • R 5 is OH, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F and Y is H.
  • R 5 is F, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • Z 1 is CH 2 CHR Z
  • Z 2 and Z 3 are each a single bond.
  • R 5 is OH.
  • R 5 is OH
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • R is F.
  • R 5 is F
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • Y is H.
  • R 5 is OH and Y is H.
  • R 5 is OH, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F and Y is H.
  • R 5 is F, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • Z 2 is CH 2 CHR Z
  • Z 1 and Z 3 are each a single bond.
  • R 5 is OH.
  • R 5 is OH
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • R is F.
  • R 5 is F
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • Y is H.
  • R 5 is OH and Y is H.
  • R 5 is OH, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is F and Y is H.
  • R 5 is F, Y is H, and R 1 , R 2 , R 3 , and R 4 are each H.
  • R 5 is OH
  • W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , Z 3 , R z , Y, n, R 6 , R 7 , and R 8 can be selected from any of the substituent groups described above.
  • R 5 is F
  • W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , Z 3 , R z , Y, n, R 6 , R 7 , and R 8 can be selected from any of the substituent groups described above.
  • a compound of Formula (I) is a compound of Formula (la)
  • each of W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Y, n, R 5 , R 6 , R 7 , and R can be selected from any of the substituent groups described above for W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Y, n, R 5 , R 6 , R 7 , and R 8 in Formula (I).
  • one of W 1 , W 2 , W 3 , and W 4 is N.
  • W 1 is N.
  • W 2 is N.
  • W 3 is N.
  • W 4 is N.
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • Y is C1-C4 alkyl or Ci- C4 haloalkyl.
  • any of the substituent groups described above for any of W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Y, n, R 5 , R 6 , R 7 , and R 8 can be combined with any of the substituent groups described above for the remainder of W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Y, n, R 5 , R 6 , R 7 , and R 8 .
  • a compound of Formula (I) is a compound of Formula (lb) or (Ic)
  • R 4 , Z 1 , Z 2 , R z , Y, n, R 5 , R 6 , R 7 , and R 8 are each as defined in Formula (I).
  • R 6 , R 7 , and R 8 can be selected from any of the substituent groups described above for W ,
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • Y is H.
  • Z 1 is CHR Z .
  • Z 1 is CH 2 CHR Z .
  • Z 2 is CHR Z . In one embodiment, Z 2 is CH 2 CHR Z .
  • W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , R z , Y, n, R 5 , R 6 , R 7 , and R 8 can be combined with any of the substituent groups described above for the remainder of W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , R z , Y, n, R 5 , R 6 , R 7 , and R 8 .
  • a compound of Formula (I) is a compound of Formula (Id)
  • R 4 , Z 3 , R z , Y, n, R 5 , R 6 , R 7 , and R 8 are each as defined in Formula (I).
  • R 7 , and R 8 can be selected from any of the substituent groups described above for W 1 , W 2 ,
  • W 1 is CR 1
  • W 2 is CR 2
  • W 3 is CR 3
  • W 4 is CR 4
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • Y is H.
  • Z 3 is CHR Z .
  • any of the substituent groups described above for any of W 1 are any of the substituent groups described above for any of W 1 ,
  • W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , Z 3 , R z , Y, n, R 5 , R 6 , R 7 , and R 8 can be combined with any of the
  • the present application relates to a com ound of Formula (II)
  • R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently H, OH, halogen, C r C 4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
  • R N is H or C1-C4 alkyl
  • R 16 is OH, halogen, C1-C4 alkoxy, or C1-C4 haloalkoxy
  • R 17 is H, OH, halogen, C1-C4 alkoxy, or C1-C4 haloalkoxy.
  • R 10 , R 11 , R 12 , and R 13 are each H.
  • At least one of R 10 , R 11 , R 12 , and R 13 is OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy. In a further embodiment, at least one of R 10 , R 11 , R 12 , and R 13 is OH. In another further embodiment, at least one of R 10 , R 11 ,
  • R , and R is halogen.
  • at least one of R , R , R , and R 1J is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy.
  • At least one of R 10 , R 11 , R 12 , and R 13 is halogen (e.g., F, CI, Br, or I). In a further embodiment, at least one of R 10 , R 11 , R 12 , and R 13 is F or CI. In a further embodiment, at least one of R 10 , R 11 , R 12 , and R 13 is F.
  • At least one of R 10 , R 11 , R 12 , and R 13 is C1-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) or C1-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is substituted with one or more halogen (e.g., F, CI, Br, or I)).
  • halogen e.g., F, CI, Br, or I
  • At least one of R 10 , R 11 , R 12 , and R 13 is C1-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i- butyl, s-butyl, or t-butyl) substituted with one or more F or CI.
  • at least one of R 10 , R 11 , R 12 , and R 13 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F.
  • At least one of R 10 , R 11 , R 12 , and R 13 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) or C1-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t- butoxy, each of which is substituted with one or more halogen (e.g., F, CI, Br, or I)).
  • halogen e.g., F, CI, Br, or I
  • At least one of R 10 , R 11 , R 12 , and R 13 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F or CI.
  • at least one of R 10 , R 11 , R 12 , and R 13 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • R 14 and R 15 are each H.
  • R is H and R is OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, C C4 haloalkyl, or C1-C4 haloalkoxy.
  • R 15 is OH.
  • R 15 is halogen (e.g., F, CI, Br, or I).
  • R 15 is F or CI.
  • R 15 is F.
  • R 15 is C1-C4 alkyl (e.g.
  • R 15 is C1-C4 haloalkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-but l, s-butyl, or t-butyl, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • halogen e.g. , F, CI, Br, or I
  • R 15 is C1-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i- butyl, s-butyl, or t-butyl) substituted with one or more F or CI.
  • R 15 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F.
  • R 15 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy).
  • R 15 is C1-C4 haloalkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, or t-butoxy, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • R 15 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F or CI.
  • R 15 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • R 15 is H and R 14 is OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, d- C4 haloalkyl, or C1-C4 haloalkoxy.
  • R 14 is OH.
  • R 14 is halogen (e.g., F, CI, Br, or I).
  • R 14 is F or CI.
  • R 14 is F.
  • R 14 is C1-C4 alkyl (e.g.
  • R 14 is C1-C4 haloalkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • halogen e.g. , F, CI, Br, or I
  • R 14 is C1-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i- butyl, s-butyl, or t-butyl) substituted with one or more F or CI.
  • R 14 is C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more F.
  • R 14 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy).
  • R 14 is C1-C4 haloalkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, or t-butoxy, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • R 14 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F or CI.
  • R 14 is C1-C4 alkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • R 14 and R 15 are independently OH, halogen (e.g. , F, CI, Br, or I), C1-C4 alkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), Ci- C4 haloalkyl (e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is substituted with one or more halogen (e.g.
  • halogen e.g. , F, CI, Br, or I
  • C1-C4 alkyl e.g. , methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-but
  • C1-C4 alkoxy e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy
  • C1-C4 haloalkoxy e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t- butoxy, each of which is substituted with one or more halogen (e.g., F, CI, Br, or I)).
  • R N is H.
  • R N is C1-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).
  • Z 4 is CH2 or CH2CH2. In a further embodiment, Z 4 is CH2CH2.
  • Z 4 is
  • R 16 is OH
  • R 16 is halogen (e.g. , F, CI, Br, or I). In a further embodiment, R 16 is F or CI. In a further embodiment, R 16 is F.
  • R 16 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) or C1-C4 haloalkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • R 16 is C1-C4 alkoxy (e.g.
  • R 16 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • R 17 is H.
  • R 17 is OH.
  • R 17 is halogen (e.g. , F, CI, Br, or I). In a further embodiment, R 17 is F or CI. In a further embodiment, R 17 is F.
  • R 17 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) or C1-C4 haloalkoxy (e.g. , methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of which is substituted with one or more halogen (e.g. , F, CI, Br, or I)).
  • R 17 is C1-C4 alkoxy (e.g.
  • R 17 is C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy) substituted with one or more F.
  • any of the substituent groups described above for any of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R N , and Z 4 can be combined with any of the substituent groups described above for the remainder of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R N , and Z 4 .
  • the compound of the present application is a compound having any one of the following structures:
  • the compounds of the present application are capable of modulating (e.g. , inhibiting or decreasing) the enzymatic activity of IDO/TDO.
  • the modulation of IDO/TDO by a compound of the present application is measured by IC5 0 .
  • the modulation of IDO/TDO by a compound of the present application is measured by EC50.
  • Potency of compounds of the present application in modulating (e.g. , inhibiting or decreasing) the enzymatic activity of IDO/TDO can be determined by EC50 value.
  • Potency of compounds of the present application in modulating (e.g. , inhibiting or decreasing) the enzymatic activity of IDO/TDO can also be determined by IC5 0 value.
  • the modulation (e.g. , inhibition) of IDO/TDO by compounds of the present application can also be measured using cellular proliferation assays where cell proliferation is dependent on IDO/TDO activity. Proliferation assays are performed at a range of compound concentrations and ECso's or ICso's are calculated.
  • the compounds of present application are more potent than one or more known modulators (e.g. , inhibitors) of IDO/TDO, such as the fused imidazole derivative compounds described in US 2014/0066625.
  • the compounds can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g., as measured by IC 50 ) than one or more known modulators (e.g., inhibitors) of
  • IDO/TDO such as he fused imidazole derivative compounds described in US 2014/0066625.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutical composition comprises one or more further active substances.
  • the compounds of the present application may be prepared by conventional methods of chemical synthesis, e.g. , those described in the examples, and starting from readily available starting materials.
  • the starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
  • the final products of the reactions described herein may be isolated by conventional techniques, e.g. , by extraction, crystallization, distillation, or chromatography.
  • the present application includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds of the present application may be prepared according to synthetic routes A, B, C, and D. These synthetic routes are given as non-limiting examples on how the compounds of the present application may be prepared.
  • Useful general procedures to prepare the compounds of the present application include general procedures illustrated below. These procedures are given as non-limiting examples on how the compounds of the present application may be prepared.
  • protecting groups may need to be employed. A skilled artisan would be able to consult many references describing such protecting group manipulations, e.g. , Wuts and Greene, "Greene's Protective Groups in Organic Synthesis," John Wiley & Sons, 4 th Edition, 2006, which is incorporated herein in its entirety by reference.
  • Compounds of Formula (la), may prepared according to Synthetic Route A, wherein R 5 is F; and W 1 , W 2 , W 3 , W 4 , Y, n, R 6 , R 7 , and R 8 are each as defined herein.
  • Compounds of Formula (la) wherein R is F can be prepared in one step by reacting the corresponding hydroxy compound with a fluorinating reagent, e.g., bis(2- methoxyethyl)aminosulfur trifluoride, i.e. , Deoxofluor®.
  • a fluorinating reagent e.g., bis(2- methoxyethyl)aminosulfur trifluoride, i.e. , Deoxofluor®.
  • Compounds of Formula (lb), may be prepared according to Synthetic Route B, wherein n is 1 and W 1 , W 2 , W 3 , W 4 , Z 1 , Y, R 5 , R 6 , R 7 , and R ! are each as defined herein.
  • Intermediate (i) may be oxidized according to procedures known in the art, e.g. , Dess-Martin periodinane oxidation, to provide ketone or aldehyde (ii).
  • An olefination reaction of (ii) with phosphonate (iii), i. e. , a Horner Wadsworth Emmons olefination, can provide enone (iv).
  • Reaction of enone (iv) with imidazole (v) can result in formation of 1,4- addition product (vi).
  • Compounds of Formula (I c), may be prepared according to Synthetic Route C, wherein Z 2 is CH 2 ; Y is H; n is 1; and W 1 , W 2 , W 3 , W 4 , R : R 6 , R 7 , and R 8 are each as defined herein.
  • Intermediate (viii) may be treated under standard alpha-bromination conditions to provide bromide (ix).
  • Reaction of bromide (ix) with imidazole (v) can result in formation of N-alkylation product (x).
  • An olefination reaction of (x) with phosphonate (iii), i.e., a Horner Wadsworth Emmons olefination can provide enone (xi).
  • a two-step procedure involving reduction of the ketone in enone (xi) with a reducing agent, e.g., sodium borohydride (NaBH 4 ), followed by a Pd-catalyzed intramolecular cross-coupling reaction can provide (xii).
  • a Pd-catalyzed hydrgenation of (xii) provides compound (xiii), which represents compounds of Formula (Ic) wherein Z 2 is CH 2i Y is H, n is 1, and R 5 is hydroxy. Additional compounds of Formula (Ic) can be made through hydroxy group functionalization reactions of (xii) to provide additional compounds of Formula Ic).
  • Compounds of Formula (la), may also prepared according to Synthetic Route D, wherein n is 1 and W 1 , W 2 , W 3 , W 4 , Y, R 5 , R 6 , R 7 , and R 1 are each as defined herein.
  • Aryl bromide (xv) and trityl (Tr)-protect imidazole (xvi) can be reacted in an intermolecular cross-coupling reaction to provide ketone or aldehyde (xvii).
  • An olefination reaction of (xvii) with phosphonate (iii), i.e. , a Homer Wadsworth Emmons olefination can provide enone (xviii).
  • a two-step procedure involving an acid-catalyzed intramolecular 1,4- addition of enone (xviii), followed by reduction of the ketone with a reducing agent, e.g. , sodium borohydride (NaBH 4 ) provides compound (xix), which represents compounds of Formula (la) wherein n is 1 and R 5 is hydroxy. Additional compounds of Formula (la) can be made through hydroxy group functionalization reactions of (xix).
  • An enzymatic assay is performed by UV absorption with either IDO or TDO (e.g. , recombinant IDOl or TD02) and a substrate of IDO or TDO (e.g., L-Tryptophan).
  • the UV absorption signal is correlated with the amount of a reaction product of IDO or TDO and the substrate (e.g., N-formylkynurenine).
  • the compounds of the present application are diluted in a suitable solvent (e.g. , 10 % DMSO) and then added to the reaction.
  • the reactions are conducted at a suitable temperature (e.g., room temperature) for certain duration to allow the enzymatic reaction of IDO or TDO.
  • the UV absorption signal is read.
  • the data are analyzed using a computer software (e.g., Graphpad Prism).
  • the absorption signal (A t ) in each data set is defined as 100% activity.
  • the absorption signal (At,) in each data set is defined as 0% activity.
  • T maximum percent activity
  • X logarithm of compound
  • Hill Slope slope factor or Hill coefficient.
  • the IC5 0 value was determined by the concentration causing a half-maximal percent activity.
  • Cells are cultured in a suitable medium (e.g., MEM/EBSS medium with 10% bovine serum, 1% Penn-strep, 1% Non-essential amino acid, 1 mM Na-pyruvate, plus 600 ⁇ g/ml of Geneticin, 5 ⁇ g/ml of Blasticidin) to ensure the IDO or TDO recombinant expression plasmid is maintained.
  • a suitable medium e.g., MEM/EBSS medium with 10% bovine serum, 1% Penn-strep, 1% Non-essential amino acid, 1 mM Na-pyruvate, plus 600 ⁇ g/ml of Geneticin, 5 ⁇ g/ml of Blasticidin
  • TCA Trigger-activated Cells
  • IDO/TDO to kynurenine IDO/TDO to kynurenine.
  • Supernatant from the culture medium is transferred and mixed with 4-(Dimethylamino) benzaldehyde in acetic acid, and incubated (e.g., at RT for 10 minutes).
  • the yellow color derived from kynurenine is recorded (e.g., by measuring absorbance at 480 nm using a microplate reader).
  • the absorbance data are analyzed using a computer software (e.g. , Graphpad Prism).
  • the absorbance (A t ) in each data set is defined as 100%.
  • the absorbance of blank medium (At,) in each data set is defined as 0%.
  • the IC50 value is determined by the concentration causing a half-maximal percent activity.
  • alkyl refers to a saturated, straight or branched hydrocarbon chain. In one embodiment, the hydrocarbon chain contains from 1 to 4 carbon atoms (C1-C4 alkyl). In one embodiment, "C1-C4 alkyl” includes methyl, ethyl, propyl, isopropyl, butyl, isobut l, secondary butyl, and tertiary butyl.
  • an “alkyl” group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH 2 -, -CH 2 CH 2 -, and -CH 2 CHC(CH 3 )-.
  • halo and halogen refer to fluoro (F), chloro (CI), bromo (Br), and iodo (I).
  • a trihalomethyl group represents, e.g., a trifluoromethyl group or a trichloromethyl group.
  • the terms “halo” and “halogen” designate fluoro or chloro.
  • the terms “halo” and “halogen” designate fluoro.
  • haloalkyl refers to an alkyl group as defined herein which is substituted with one or more fluoro (F), chloro (CI), bromo (Br), and/or iodo (I).
  • a haloalkyl group is a fluoroalkyl group that is substituted with one fluoro.
  • a fluoroalkyl group is substituted with two fluoros.
  • a fluoroalkyl group is substituted with three or more fluoros.
  • fluoroalkyl is perfluorinated, which, as used herein, refers to an alkyl group as defined herein wherein all hydrogen atoms are replaced by fluoro atoms.
  • a fluoroalkyl group is trifluoromethyl.
  • a fluoroalkyl group is
  • a fluoroalkyl group is heptafluoropropyl.
  • a haloalkyl group is chloromethyl, trichloromethyl, trifluoromethyl, 2- fluoroethyl, pentafluoroethyl, or heptafluoropropyl.
  • alkoxy refers to an "alkyl-O-" group, wherein alkyl is as defined herein.
  • an alkoxy group is methoxy, ethoxy, propoxy, 2- propoxy, butoxy, or tert-butoxy.
  • haloalkoxy refers to a "haloalkyl-O" group, wherein haloalkyl is as defined herein.
  • hydroxy as used herein, means an OH group.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting the IDO enzyme with a compound includes the administration of a compound described herein to an individual or patient, such as a human, having IDO, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing the IDO enzyme.
  • mice refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • a therapeutically effective amount can be an amount suitable for (1) preventing the disease, for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease, for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; or (3) ameliorating the disease, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual who is experiencing
  • treatment means (i) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptom of the disease, condition or disorder (e.g. , reversing or improving the pathology and/or symptom) such as decreasing the severity of disease; or (ii) eliciting the referenced biological effect (e.g. , IDO modulation or tryptophan degradation inhibition).
  • ameliorating the referenced disease state for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptom of the disease, condition or disorder (e.g. , reversing or improving the pathology and/or symptom) such as decreasing the severity of disease; or (ii) eliciting the referenced biological effect (e.g. , IDO modulation or tryptophan degradation inhibition).
  • the compounds of the present application may be provided in any form suitable for the intended administration, in particular including pharmaceutically acceptable salts and solvates of the compound of the present application.
  • Pharmaceutically acceptable salts refer to salts of the compounds of the present application, which are considered to be acceptable for clinical and/or veterinary use.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present application with a mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts, respectively.
  • any salt is not of a critical nature, so long as the salt as a whole is pharmaceutically acceptable and as long as the counter-ion does not contribute undesired qualities to the salt as a whole.
  • These salts may be prepared by methods known to the skilled person.
  • Pharmaceutically acceptable salts are, e.g., those described and discussed in Remington's Pharmaceutical Sciences, 17. Ed. Alfonso R. Gennaro (Ed.), Mack Publishing Company, Easton, PA, U.S.A., 1985 and more recent editions and in Encyclopedia of Pharmaceutical Technology.
  • Examples of pharmaceutically acceptable addition salts include acid addition salts formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric, or phosphoric acid; and organic acids e.g., succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, gly colic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic and galacturonic acid; and arylsulfonic, for example benzenes
  • naphthalenesulfonic acid and base addition salts formed with alkali metals and alkaline earth metals and organic bases such as ⁇ , ⁇ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and internally formed salts.
  • alkali metals and alkaline earth metals and organic bases such as ⁇ , ⁇ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and internally formed salts.
  • the compound of the present application may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvent such as water, ethanol, and the like.
  • Dissoluble forms may also include hydrated forms such as the mono- hydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like.
  • the compounds of the present application may exist as geometric isomers (e.g., cis-trans isomers), optical isomers, or stereoisomers, such as diastereomers, as well as tautomers. Accordingly, it should be understood that the definition of the compounds of the present application, or a
  • pharmaceutically acceptable salt or solvate thereof includes each and every individual isomer corresponding to the structural formula of the compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, including cis-trans isomers, stereoisomers and tautomers, as well as racemic mixtures of these.
  • the definition of the compounds of the present application, or a pharmaceutically acceptable salt or solvate thereof is also intended to encompass all R- and S -isomers of a chemical structure in any ratio, e.g., with enrichment (i.e. , enantiomeric excess or diastereomeric excess) of one of the possible isomers and corresponding smaller ratios of other isomers.
  • Diastereoisomers i.e. , non-superimposable stereochemical isomers
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base.
  • appropriate acids include, without limitation, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • the mixture of diastereomers can be separated by crystallization followed by liberation of the optically active bases from these salts.
  • An alternative process for separation of optical isomers includes the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the present application, or a pharmaceutically acceptable salt or solvate thereof, with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain the enantiomerically pure compound.
  • pharmaceutically acceptable salt or solvate thereof can likewise be obtained by utilizing optically active starting materials and/or by utilizing a chiral catalyst. These isomers may be in the form of a free acid, a free base, an ester or a salt. Examples of chiral separation techniques are given in Chiral Separation Techniques, A Practical Approach, 2 nd ed. by G. Subramanian, Wiley-VCH, 2001.
  • the compounds and pharmaceutical compositions described herein can modulate activity of the IDO/TDO.
  • modulate is meant to refer to an ability to change (e.g., decrease) the activity of an enzyme or receptor.
  • compounds described herein can be used in methods of modulating IDO/TDO by contacting the enzyme with any one or more of the compounds or compositions described herein.
  • the compounds described herein can act as inhibitors of IDO/TDO.
  • the compounds described herein can be used to modulate activity of IDO/TDO in cell or in an individual in need of modulation of the enzyme by administering a modulating (e.g., inhibiting) amount of a compound described herein.
  • methods of inhibiting the degradation of tryptophan and preventing the production of N-formylkynurenine in a system containing cells expressing IDO/TDO such as a tissue, living organism, or cell culture.
  • methods of altering (e.g. , increasing) extracellular tryptophan levels in a mammal comprise administering an effective amount of a compound or pharmaceutical composition provided herein. Methods of measuring tryptophan levels and tryptophan degradation are routine in the art.
  • IDO/TDO or treating a disease or condition in which IDO/TDO plays a role, in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.
  • Examples of a disease of condition in which IDO/TDO plays a role include cancer, viral infection such as HIV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and systemic lupus erythematosusor.
  • Example cancers include cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.
  • the immunosuppression is associated with an infectious disease or cancer.
  • the immunosuppression is associated with an infectious disease
  • the infectious disease is a viral infection selected from the group consisting of hepatitis C virus (HCV), human papilloma irus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, varicella zoster virus, coxsackie virus, and human immunodeficiency virus (HIV)
  • the immunosuppression is immunosuppression associated with HTV-I infection.
  • the immunosuppression is associated with a cancer.
  • the imnumosuppression is tumor-specific immunosuppression associated with cancer.
  • the immunosuppression is associated with a cancer, wherein the cancer is colon, pancreas, breast, prostate, iung, bram, ovary, cervix, testes, renal, head, or neck cancer, or lymphoma, leukemia, or melanoma.
  • the present application provides the use of a compound or pharmaceutical composition provided herein, for the preparation of a medicament for the treatment of immunosuppression mediated by IDO/TDG or a disease or condition in which IDO/TDO plays a role.
  • the present application provides the use of a compound or pharmaceutical composition provided herein, for the preparation of a medicament for the treatment of immunosuppression associated with cancer, infectious diseases, or viral infections.
  • the present application provides the use of a compound or pharmaceutical composition provided herein, for the preparation of a medicament for the treatment of tumor-specific immunosuppression associated with cancer (e.g. , cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, or head and neck, or lymphoma, leukemia, melanoma, and the like).
  • cancer e.g. , cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, or head and neck, or lymphoma, leukemia, melanoma, and the like.
  • the present application provides the use of a compound or pharmaceutical composition provided herein, for the preparation of a medicament for the treatment of infectious diseases where the infectious disease is a viral infection.
  • the viral infection is selected from the group consisting of: influenza, hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein- Barr vims (EBV), varicella zoster virus, poliovirus, coxsackie virus, and human
  • HIV immunodeficiency virus
  • HIV immunodeficiency virus
  • cancer refers to any cancer caused by the proliferation of neoplastic cells, such as solid tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like.
  • cancers that may be treated by the compounds, compositions, and methods of the present application include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma, (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
  • adenocarcinoma insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma
  • small bowel adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);
  • Genitourinary tract kidney (adenocarcinoma, Wilm's tumor, nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcfhoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma
  • osteogenic sarcoma osteogenic sarcoma
  • fibrosarcoma malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma
  • malignant lymphoma reticulum cell sarcoma
  • multiple myeloma malignant giant cell tumor chordoma
  • osteochronfroma osteocartilaginous exostoses
  • Nervous system skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord (neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ova
  • cystadenocarcinoma mucinous cystadenocarcinoma, unclassified carcinoma, granulosa- thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplasia syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin
  • compounds, compositions, and methods of the present application are useful in the treatment of one or more cancers selected from the group consisting of: leukemias including acute leukemias and chronic leukemias such as acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and Hairy Cell Leukemia;
  • leukemias including acute leukemias and chronic leukemias such as acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and Hairy Cell Leukemia;
  • ALL acute lymphocytic leukemia
  • AML Acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • Hairy Cell Leukemia hairy Cell Leukemia
  • lymphomas such as cutaneous T-cell lymphomas (CTCL), non-cutaneous peripheral T-cell lymphomas, lymphomas associated with human T- cell lymphotrophic virus (HTLV) such as adult T-cell leukemia/Iymphoma (ATLL), Hodgkin's disease and non-Hodgkin's lymphomas, large-cell lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma;
  • CTCL cutaneous T-cell lymphomas
  • HTLV human T- cell lymphotrophic virus
  • ATLL adult T-cell leukemia/Iymphoma
  • Hodgkin's disease and non-Hodgkin's lymphomas large-cell lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • Burkitt's lymphoma Burkitt's lymphoma
  • mesothelioma primary central nervous system (CNS) lymphoma; multiple myeloma;
  • childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genito-urinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), lung cancer, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, liver cancer and thyroid cancer.
  • head and neck cancers e.g., oral, laryngeal and esophageal
  • genito-urinary cancers e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon
  • lung cancer breast cancer
  • pancreatic cancer melanoma and other skin cancers
  • stomach cancer brain tumors
  • compounds, compositions, and methods of the present application are useful for the treatment of squamous cell carcinomas.
  • squamous cell carcinomas are cancers of the carcinoma type of squamous epithelium that may occur in many different organs, including the skin, lips, mouth, esophagus, urinary bladder, prostate, lungs, vagina, and cervix; brain cancer, that is neuroblastoma, glioblastoma and other malignant and benign brain tumors; breast cancer, pancreatic cancer, and multiple myeloma.
  • the compounds of the present application, or a pharmaceutically acceptable salt or solvate thereof, as defined herein are useful for treatment of brain cancer, tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genito-urinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), and breast cancer.
  • head and neck cancers e.g., oral, laryngeal and esophageal
  • genito-urinary cancers e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon
  • the disease to be treated by compounds, compositions, and methods of the present application is selected from persistent proliferative or hyperproliferative conditions such as angiogenesis, such as psoriasis; Kaposi's sarcoma; restenosis, e.g., stent-induced restenosis; endometriosis; Hodgkin's disease; leukemia;
  • persistent proliferative or hyperproliferative conditions such as angiogenesis, such as psoriasis; Kaposi's sarcoma; restenosis, e.g., stent-induced restenosis; endometriosis; Hodgkin's disease; leukemia;
  • hemangioma hemangioma
  • angiofibroma eye diseases, such as neovascular glaucoma
  • renal diseases such as glomerulonephritis; malignant nephrosclerosis; thrombotic microangiopathic syndromes; transplant rejections and glomerulopathy
  • fibrotic diseases such as cirrhosis of the liver
  • mesangial cell-proliferative diseases injuries of the nerve tissue; and inhibiting the re- occlusion of vessels after balloon catheter treatment, for use in vascular prosthetics or after inserting mechanical devices for holding vessels open, such as, e.g. , stents, as immune- suppressants, as an aid in scar-free wound healing, and treating age spots and contact dermatitis.
  • compositions comprising a therapeutically effective amount of at least one compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in combination with at least one further therapeutic agent (e.g. , anti-viral agent,
  • chemotherapeutic or other anti-cancer agent a pharmaceutically acceptable excipient, carrier or diluent.
  • a patient undergoing or having completed a course of chemotherapy and/or radiation therapy for the treatment of a disease state can benefit from administration of a therapeutically effective amount of a compound or composition recited herein for inhibiting immunosuppression resulting from the disease state and/or treatment thereof.
  • a pharmaceutical composition comprising at, as an active ingredient, at least one compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, as defined herein and optionally one or more pharmaceutically acceptable excipients, diluents and/or carriers.
  • the compounds of the present application, or a pharmaceutically acceptable salt or solvate thereof may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses.
  • Suitable pharmaceutically acceptable carriers, diluents and excipients include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • compositions may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21st Edition, 2000, Lippincott Williams & Wilkins.
  • compositions formed by combining a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, as defined herein with pharmaceutically acceptable carriers, diluents or excipients can be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, suppositories, injectable solutions and the like.
  • the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • compositions may be specifically prepared for administration by any suitable route such as the oral and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be prepared so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • a compound of the present application may suitably be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water or the like.
  • an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water or the like.
  • suitable binders, lubricants, disintegrating agents, flavoring agents and colorants may be added to the mixture, as appropriate.
  • Suitable binders include, e.g., lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes or the like.
  • Lubricants include, e.g., sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like.
  • Disintegrating agents include, e.g. , starch, methyl cellulose, agar, bentonite, xanthan gum, sodium starch glycolate,
  • the active compound of the present application, or a pharmaceutically acceptable salt or solvate thereof is mixed with one or more excipients, such as the ones described above, and other pharmaceutical diluents such as water to make a solid pre-formulation composition containing a homogenous mixture of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof.
  • homogenous is understood to mean that the compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, is dispersed evenly throughout the composition so that the composition may readily be subdivided into equally effective unit dosage forms such as tablets or capsules.
  • Liquid compositions for either oral or parenteral administration of the compound of the present application, or a pharmaceutically acceptable salt or solvate thereof include, e.g. , aqueous solutions, syrups, elixirs, aqueous or oil suspensions and emulsion with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin,
  • methylcellulose or polyvinylpyrrolidone methylcellulose or polyvinylpyrrolidone.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • solutions containing a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed.
  • Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes.
  • compositions of a compound of the present application may include one or more additional ingredients such as diluents, buffers, flavoring agents, colorant, surface active agents, thickeners, preservatives, e.g., methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • additional ingredients such as diluents, buffers, flavoring agents, colorant, surface active agents, thickeners, preservatives, e.g., methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • a suitable dosage of the compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, will depend on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practicing physician.
  • the compound may be administered for example either orally, parenterally or topically according to different dosing schedules, e.g. , bi-daily, daily or with intervals, such as weekly intervals.
  • a single dose will be in the range from 0.01 to 100 mg/kg body weight, preferably from about 0.05 to 75 mg/kg body weight, more preferably between 0.1 to 50 mg/kg body weight, and most preferably between 0.1 to 25 mg/kg body weight.
  • the compound may be administered as a bolus (i.e.
  • the entire daily dose is administered at once) or in divided doses two or more times a day. Variations based on the aforementioned dosage ranges may be made by a physician of ordinary skill taking into account known considerations such as weight, age, and condition of the person being treated, the severity of the affliction, and the particular route of administration.
  • the compounds of the present application may also be prepared in a pharmaceutical composition comprising one or more further active substances alone, or in combination with pharmaceutically acceptable carriers, diluents, or excipients in either single or multiple doses.
  • suitable pharmaceutical composition comprising one or more further active substances alone, or in combination with pharmaceutically acceptable carriers, diluents, or excipients in either single or multiple doses.
  • pharmaceutically acceptable carriers, diluents and excipients are as described herein above, and the one or more further active substances may be any active substances.
  • compositions described herein generally comprise a combination of a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by U.S. regulatory requirements at the time of filing this application.
  • the composition if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g., tablet, capsules, etc.).
  • compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • topical including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal
  • ocular oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions can contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound in preparing a formulation, can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein.
  • a solid preformulation composition containing a homogeneous mixture of a compound described herein.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.
  • the tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions administered to a patient can be in the form of
  • compositions described above can be sterilized by conventional sterilization techniques, or may be sterile filtered.
  • Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the compounds described herein can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, antiinflammatory agents and the like.
  • kits useful for example, in the treatment or prevention of diseases or disorders in which IDO/TDO plays a role, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for
  • administration, and/or guidelines for mixing the components can also be included in the kit.
  • “combination therapy” or “co-therapy” includes the administration of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, and at least a second agent, to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” may be, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combination of the present application.
  • Combination therapy is intended to embrace administration of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, and at least a second agent in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered through any other route (e.g. , orally, subcutaneously, or
  • a first therapeutic agent of the combination selected may be administered orally while the other therapeutic agents of the combination may be
  • any other route e.g. , intravenously, subcutaneously, or
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • Combination therapy also embraces the administration of the therapeutic agents as described herein in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment).
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • the compound of the application can be administered in therapeutically effective amounts in a combination with one or more therapeutic agents.
  • synergistic effects can occur with another therapeutic agent.
  • the second therapeutic agent can be selected from a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or
  • immunosuppressive agent a neurotrophic factor
  • an agent for treating cardiovascular disease an agent for treating destructive bone disorders
  • an anti-viral agent an agent for treating blood disorders
  • an agent for treating immunodeficiency disorders an agent for treating immunodeficiency disorders.
  • the additional therapeutic agent is an anti-cancer agent, an anti-proliferative agent, or a chemotherapeutic agent.
  • the additional therapeutic agent is selected from cisplatin (Platino®), carboplatin (Paraplatin®), oxaliplatin (Eloxatin®), daunomycin
  • the additional therapeutic agent is selected from anticancer antibody or immunoglobulin therapies or agents including, but not limited to, ipilimumab (Yervoy®), tremelimumab, antibodies or agents that target programmed death receptor 1 [PD-1] or programmed death ligand 1 [PD-L1], e.g., CT-011 (Curetech), BMS- 936558 (Bristol-Myers Squibb), BMS-936559 (Bristol-Myers Squibb), AMP-224 (Amplimmune/Glaxo-Smithkline), pembrolizumab (Merck & Co.), MPDL3280A (Roche), MGA-271 (Macrogenics), dacarbazine, Lambrolizumab (MK-3475), MSB0010718C (MerckSerono), and MEDI-4736 (Medlmmune).
  • ipilimumab Yervoy®
  • tremelimumab antibodies or agents that target programme
  • the additional therapeutic agent is selected from a CTLA4 agent (e.g., ipilimumab (BMS)); GITR agent (e.g. , MK-4166 (MSD)); vaccines (e.g. , Nanovacc (MerckSerono), Stimuvax (MerckSerono), Sipuleucel-T (Dendron); and a SOC agent (e.g. , radiation, docetaxel, Temozolomide (MSD), Gemcitibine, or Paclitaxel).
  • a CTLA4 agent e.g., ipilimumab (BMS)
  • GITR agent e.g. , MK-4166 (MSD)
  • vaccines e.g. , Nanovacc (MerckSerono), Stimuvax (MerckSerono), Sipuleucel-T (Dendron)
  • SOC agent e.g. , radiation, docetaxel, Temozo
  • the additional therapeutic agent is an immune enhancer such as a vaccine, immune-stimulating antibody, immunoglobulin, agent or adjuvant including, but not limited to, sipuleucel-t (Provenge®), BMS-663513 (Bristol-Myers Squibb), CP-870893
  • an immune enhancer such as a vaccine, immune-stimulating antibody, immunoglobulin, agent or adjuvant including, but not limited to, sipuleucel-t (Provenge®), BMS-663513 (Bristol-Myers Squibb), CP-870893
  • the additional therapeutic agent is an anti-PD-1 or anti-PD-Ll agent and is administered together with a compound of the present application as a single dosage form.
  • the additional therapeutic agent is an anti-PD- 1 or anti-PD-Ll agent and is administered separately from a compound of the present application as part of a multiple dosage form.
  • the anti-PD-1 or anti- PD-Ll is administered as an intravenous infusion.
  • more than one additional therapeutic agents are used and are administered together with a compound of the present application as a single dosage form. In certain embodiments, more than one additional therapeutic agents are used and are administered separately from a compound of the present application as part of a multiple dosage form. In certain embodiments, the more than one additional therapeutic agents are anti-PD-1 or anti-PD-Ll agents. In certain embodiments, the anti-PD-1 or anti-PD-Ll agents are administered as an intravenous infusion.
  • cancer therapies or anticancer agents that may be used in combination with a compound of the present application include surgery, radiotherapy (e.g. , gamma- radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachy therapy, low-dose radiotherapy, and systemic radioactive isotopes), immune response modifiers such as chemokine receptor antagonists, chemokines and cytokines (e.g., interferons, interleukins, tumour necrosis factor (TNF), and GM-CSF)), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g. antimetics, steroids, antiinflammatory agents), and other approved chemotherapeutic drugs.
  • radiotherapy e.g. , gamma- radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachy therapy, low-dose radiotherapy, and systemic radioactive isotopes
  • immune response modifiers such as chemokine receptor antagonists, chemokines and cytok
  • a compound of the present application may also be useful for treating cancer in combination with or in addition to any of the following standard of care (SOC) therapeutic agents: abarelix (Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busul
  • SOC
  • cisplatin Platinol®
  • cladribine Leustatin®, 2-CdA®
  • clofarabine Clolar®
  • cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®);
  • cyclophosphamide Cytoxan Tablet®
  • cytarabine Cytosar-U®
  • cytarabine liposomal DepoCyt®
  • dacarbazine DTIC-Dome®
  • dactinomycin, actinomycin D Cosmegen®
  • Darbepoetin alfa Aranesp®
  • daunorubicin liposomal DanuoXome®
  • Denileukin diftitox Ontak®
  • dexrazoxane Zinecard®
  • docetaxel Taxotere®
  • doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate
  • IFEX® ifosfamide
  • Gleevec® imatinib mesylate
  • Roferon A® interferon alfa 2a
  • Interferon alfa-2b Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®);
  • letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate
  • Oprelvekin Neurone®
  • paclitaxel Paclitaxel
  • Tuxol® paclitaxel protein-bound particles
  • Abraxane® palifermin
  • pamidronate Alcosine®
  • pegademase Adagen (Pegademase Bovine)®
  • pegaspargase Oncaspar®
  • Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);
  • pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium
  • tamoxifen Nolvadex®
  • temozolomide Temodar®
  • teniposide VM-26 (Vumon®)
  • testolactone Teslac®
  • thioguanine 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®);
  • vincristine Oncovin®
  • vinorelbine Navelbine®
  • zoledronate Zometa
  • vorinostat Zaolinza®
  • the additional therapeutic agent is selected from an antibiotic, a vasopressor, a steroid, an inotrope, an anti-thrombotic agent, a sedative, opioids, and an anesthetic.
  • the additional therapeutic agent is selected from cephalosporins, macrolides, penams, beta-lactamase inhibitors, aminoglycoside antibiotics, fluoroquinolone antibiotics, glycopeptide antibiotics, penems, monobactams, carbapenmems, nitroimidazole antibiotics, lincosamide antibiotics, vasopressors, positive inotropic agents, steroids, benzodiazepines, phenol, alpha2-adrenergic receptor agonists, GABA-A receptor modulators, anti-thrombotic agents, anesthetics, and opiods.
  • the additional therapeutic agent is Alatrofloxacin
  • Amifloxacin Balofloxacin, Besifloxacin, Ciprofloxacin, Clinafloxacin, Danofloxacin, Delafloxacin, Difloxacin, Enoxacin, Enrofloxacin, Fleroxacin, Garenoxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Marbofloxacin, Moxifloxacin, Nadifloxacin, Norfloxacin, Ofloxacin, Orbifloxacin, Pazufloxacin, Pefloxacin, Prulifloxacin, Rufloxacin, Sitafloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin, Trovafloxacin, Vancomycin, Teicoplanin, Telavancin, Bleomycin, Ramoplanin, Decaplanin, Azanidazole, Dimetridazole, Metron
  • Cefpodoxime Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Oxacephem, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline fosamil,
  • Amoxicillin Ampicillin, Epicillin, Carbenicillin, e.g. , Carindacillin, Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam, Sulbenicillin, Benylpenicillin,
  • Clometocillin Benzathine benylpenecillin, Procaine benylpenecillin, Azidocillin,
  • Penamecillin Phenoxymethylpenecillin, Propicillin, Benzathine phenoxymthylpenecillin, Pheneticillin, Cloxacillin, Oxacillin, Meticillin, Nafcillin, Faropenem, Aztreonam,
  • Panipenem Penam, Clavam, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Kitasamycin, Midecamycin, Roxithromycin, Troleandomycin, Ansamycin, Carbomycin, Cethromycin, Oleandomycin, Solithromycin, Spiramycin, Telithromycin, Tylosin, Amikacin, Arbekcacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Paromycin,
  • Rhodostreptomycin Streptomycin, Tobramycin, Apramycin, Norepinephrine, Epinephrine, Phenylepinephrine, Dopamine, Vasopressin, Berberine, Calcium, Omecamtiv, Dobutamine, Dopexamine, Isoprenaline, Phenylepinephrine, Dogoxin, Prostaglandins, Enoximone, Milrinone, Amrinone, Theophylline, Digitalis, Glucagon, Hydrocortisone, Cortisone, Fluorocortisone, Heparin, Diazepam, Lorazepam, Midazolam, Propofol, Dexmedetomidine, Etomidate, Fentanyl, Hydromorphone, Morphine, Meperidine, Remifentanil, or Ketamine.
  • the present application relates to a method for modulating (e.g., inhibiting) IDO/TDO or for modulating (e.g. , inhibiting) the degradation of tryptophan and the production of N-formylkynurenine, comprising administering an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in combination with at least a second agent (e.g., as described herein).
  • a second agent e.g., as described herein
  • the present application relates to a method for treating immunosuppression mediated by IDO/TDO or a disease or condition in which IDO/TDO plays a role in a subject in need thereof, comprising administering an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in a combinational therapy together with at least a second agent (e.g., as described herein).
  • a second agent e.g., as described herein.
  • the present application relates to a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in combination with at least a second agent (e.g., as described herein) in modulating (e.g. , inhibiting) IDO/TDO or modulating (e.g. , inhibiting) the degradation of tryptophan and the production of N-formylkynurenine.
  • a second agent e.g., as described herein
  • the present application relates to a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in a combinational therapy together with at least a second agent (e.g., as described herein) in treating immunosuppression mediated by IDO/TDO or a disease or condition in which IDO/TDO plays a role in a subject in need thereof.
  • a second agent e.g., as described herein
  • the present application relates to use of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a
  • compositions thereof for use in combination with at least a second agent (e.g. , as described herein) in the manufacture of a medicament for modulating (e.g., inhibiting) IDO/TDO or modulating (e.g. , inhibiting) the degradation of tryptophan and the production of N-formylkynurenine.
  • a second agent e.g. , as described herein
  • the present application relates to use of a compound of the present application, or a pharmaceutically acceptable salt or solvate thereof, or a
  • compositions thereof for use in a combinational therapy together with at least a second agent (e.g. , as described herein) in the manufacture of a medicament for treating immunosuppression mediated by IDO/TDO or a disease or condition in which IDO/TDO plays a role in a subject in need thereof,
  • a second agent e.g. , as described herein
  • Step 1 Synthesis of 4-(2-bromophenyl)-l-cyclohexyl-3-(lH-imidazol-l- yl)butan-l-one
  • Step 2 Synthesis of l-cyclohexyl-2-(5, 6-dihydroimidazo[5, l-aJisoquinolin-5- ljethanol
  • Step 1 Synthesis of 2-bromo-l-(2-iodophenyl)ethanone
  • Step 2 Synthesis of 2-(lH-imidazol-l-yl)-l-(2-iodophenyl)ethanone
  • Step 3 Synthesis of l-cyclohexyl-4-(lH-imidazol-l-yl)-3-(2-iodophenyl)but-2- -l-one
  • Step 4 Synthesis of l-cyclohexyl-4-(lH-imidazol-l-yl)-3-(2-iodophenyl)but-3- en-l-ol
  • Step 6 Synthesis of l-cyclohexyl-2-(5, 6-dihydroimidazo[5, l-a]isoquinolin-6- yljethanol
  • Step 1 Synthesis of 3-(l-trityl-lH-imidazol-4-yl)isonicotinaldehyde
  • Step 2 Synthesis of (E)-l-cyclohexyl-3-(3-(l-trityl-lH-imidazol-4-yl)pyridin- 4-yl)prop-2-en-l-one
  • Step 2 Synthesis of (l-cyclohexyl-2-(5H-imidazo[l',5': l,2]pyrrolo[3,4- c ]pyridin-5-yl) ethanone
  • Step 2 Synthesis of l-cyclohexyl-2-( 5H-imidazo[ 1 5':1,2 ]pyrrolo[ 3, 4- c ]pyridin-5-yl) ethanol
  • the assay was performed by UV absorption using either recombinant IDOl or
  • the UV absorption signal at 321 nm was correlated with the amount of N-formylkynurenine reaction product of IDOl and TD02.
  • IDOl Assay All of the reactions were conducted at room temperature. The
  • reaction mixture in IDO Assay Buffer contains 40 nM IDOl, the indicated amount of the compound, 900 ⁇ tryptophan, and the coupled reaction components.
  • the reaction mixture was incubated for 180 min prior to reading of the UV absorption signal.
  • negative control (blank)
  • 5 ⁇ of the assay buffer was added instead of the IDOl.
  • TD02 Assay All of the reactions were conducted at room temperature. The
  • reaction mixture in TD02 Assay Buffer contains 50 nM TD02, the indicated amount of the compound, 200 ⁇ tryptophan, and the coupled reaction components. The reaction mixture was incubated for 60 min prior to reading of the UV absorption signal. For the negative control (blank), 5 ⁇ of the assay buffer was added instead of the TD02.
  • T maximum percent activity
  • X logarithm of compound
  • Hill Slope slope factor or Hill coefficient.
  • the IC5 0 value was determined by the concentration causing a half-maximal percent activity.

Abstract

La présente invention concerne des composés et des procédés de modulation (par exemple, d'inhibition) de l'enzyme indole-amine 2,3-dioxygénase et/ou tryptophane 2,3-dioxygénase (IDO/TDO), ainsi que des méthodes de traitement de maladies et de troubles dans lesquels IDO/TDO joue un rôle. La présente invention concerne des composés de formule (I) ou (II) :
PCT/US2016/059307 2015-10-29 2016-10-28 Dérivés d'imidazole fusionnés utilisés comme inhibiteurs d'ido/tdo WO2017075341A1 (fr)

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